Cell therapy in Huntington’s disease

Abstract

Summary: Huntington's disease is an autosomal dominant genetic disease, which results in progressive neuronal degeneration in the neostriatum and neocortex, and associated functional impairments in motor, cognitive, and psychiatric domains. Although the genetic mutation is identified, involving an abnormal CAG expansion within the htt gene on chromosome 4, the mechanism by which this leads to neuronal cell death and the question of why striatal neurones are targeted both remain unknown. Thus, in addition to the search for molecular and genetic strategies to inhibit development of the disease, we still need to identify effective strategies for cellular repair in affected individuals. Aspects of the human neuropathology can be well modeled by excitotoxic or metabolic lesions in experimental animals, and in transgenic mice carrying the htt mutation, providing the basis for testing alternative therapeutic strategies. The rationale and efficacy of alternative cell therapies are reviewed, including transplantation repair with embryonic striatal tissues, expansion and differentiation of striatal-like cells from stem cells, and in vivo and ex vivo gene therapy for delivery of neuroprotective growth factor molecules. Pilot and experimental clinical trials of several approaches are now also underway, and the alternative strategies are compared.

BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease

“…However, this proved to be too invasive for the endogenous cells and not sufficiently diffusible in the striatum. 21,25,28 Grafting of engineered cells for the release of protective molecules has also been proposed as one of the most promising therapeutic tools for HD. 29 We have previously shown that BDNF-overexpressing cell lines prevent the death of striatal projecting neurons in a rat model of HD.…”

“…26,27 However, vector and virus toxicity, tumorigenesis and uncontrolled gene expression are often important problems to be solved. 21,25,28 Cell therapy has emerged as a putative tool to treat neurodegenerative diseases, genetically engineered cells being one of the most frequently considered strategies (for review see Dunnett and Rosser 29 ). In particular, engineered astrocytes could be good candidates to release neurotrophic factors.…”

The Colayer Method as an Efficient Way to Genetically Modify Mesencephalic Progenitor Cells Transplanted into 6-OHDA Rat Model of Parkinson's Disease

“…adults (7,35), NPCs are of high interest to develop restopresent here a promising approach to increase graft survival and to identify transplanted cells also months ration strategies further (15,30,34,41). However, irrespective of the cell source, the major problem of the after transplantation.…”

Embryonic Stem Cells Overexpressing the Recognition Molecules L1 and Tenascin-R Enhance Regeneration in Mouse Models of Acute and Chronic Neurological Disorders

“…For instance, neurons isolated from mouse or human embryonic mesencephalon have been widely used for transplantation in the 6-OHDA-lesion rodent animal model of Parkinson´s disease (Grealish et al 2010;Brundin et al, 1986), and human fetal cells from the ventral mesencephalon have also been used in several clinical trials in Parkinson patients, some of which showed significant clinical improvement (Mendez et al, 2005;Astradsson et al, 2008;Mendez et al, 2008;Lindvall and Kokaia, 2009). Similarly, fetal striatal neurons have been successfully transplanted into animal models of Huntington´s disease to replace damaged GABAergic medium-sized spiny projection neurons in the host striatum (Isacson et al, 1986;Dunnett and Rosser, 2007), and clinical trials have shown improvement in some of the transplanted patients suffering from Huntington's disease (Philpott et al, 1997;Dunnett and Rosser, 2004). However, alternative cellular sources are required because of the limited availability of fetal tissue.…”